The objective of this proposal is to define the biochemical and hormonal parameters which determine the physiological regulation of ketogenesis in man. The focus of attention will be directed toward the pathophysiology of human diabetic ketosis and ketoacidosis. The experimental approach utilizes methodology designed to separate and investigate the role of substrate availability; viz., free fatty acids (FFA), for ketogenesis; as well as the role of hormone regulation of FFA substrate conversion to ketones: viz., role of glucagon and of insulin on these events. Studies are directed in parallel at both human subjects and rat models of the human counterparts. In normal and insulin-deficient diabetic patients, a series of studies will be performed in which FFA concentration will be either increased acutely with intravenous heparin, or decreased chronically with antilipolytic agents (clofibrate, etc.) Utilizing this setting of altered FFA substrate availability for ketogenesis, we will then examine the augmentation or suppression of substrate conversion to ketones utilizing exogenous hormone infusion to produce physiological concentrations. Comparisons with these human studies will be made with the normal and diabetic rat in which hormone secretion (insulin and glucagon) has been acutely altered by somatostatin infusion. It is anticipated that these investigations will further define the interrelationships between free fatty acid availability and hormone regulation of free fatty acid conversion to ketones, and also elucidate the importance of these two events to the development of ketosis and ketoacidosis in human diabetes mellitus. Finally, by utilizing specific pharmacologic agents currently available to physicians to modify the FFA-lipid axis, it is anticipated that an increased appreciation of the potential role of drug therapy in managing ketoacidotic diabetes mellitus will be obtained.